Discovery of Nanomolar DCAF1 Small Molecule Ligands.

DCAF1 is a substrate receptor of two distinct E3 ligases (CRL4DCAF1 and EDVP), plays a critical physiological role in protein degradation, and is considered a drug target for various cancers. Antagonists of DCAF1 could be used toward the development of therapeutics for cancers and viral treatments. We used the WDR domain of DCAF1 to screen a 114-billion-compound DNA encoded library (DEL) and identified candidate compounds using similarity search and machine learning. This led to the discovery of a compound (Z1391232269) with an SPR KD of 11 µM. Structure-guided hit optimization led to the discovery of OICR-8268 (26e) with an SPR KD of 38 nM and cellular target engagement with EC50 of 10 µM as measured by cellular thermal shift assay (CETSA). OICR-8268 is an excellent tool compound to enable the development of next-generation DCAF1 ligands toward cancer therapeutics, further investigation of DCAF1 functions in cells, and the development of DCAF1-based PROTACs.

Can We Innovatively Modify the Surgical Helmets to Protect Against the Droplets and Aerosols of COVID-19?

We tested the filtration efficiency of Stryker T5 surgical helmets with and without the addition of a filter medium. Two particle counters were used to count the particles of sizes .5 µm, 1 µm, and 5 µm, both inside and outside the Stryker T5 helmet, concurrently. The total inward leakage (TIL) for the helmet with and without the filter was zero for 5 µm particles at all time points. The TIL (3.4) for the .5 µm particles decreased significantly after application of the filter (1.7; P = .007). We recommend that an N95 should be used inside the helmet system.

Results and complications of head-preserving techniques in chronic neglected shoulder dislocation: a systematic review.

BACKGROUND: Humeral head-preserving procedures may be needed for chronic neglected shoulder dislocation because the presenting age of the patient is often reported to be less than 45 years. The aim of this systematic review was to evaluate the results of the various head-preserving procedures for chronic anterior dislocation (CAD) and chronic posterior dislocation (CPD). This review also aimed to evaluate the results of conservative neglect for CAD. METHODS: PubMed, Embase, and Cochrane library databases were queried for studies that reported on results of head-preserving procedures for CAD or CPD and for studies that reported on the results of conservative neglect for CAD. Case reports, review articles, acute dislocations, and fracture-dislocations were excluded. The results of the different techniques were pooled for further evaluation. RESULTS: Seventeen studies were selected for qualitative analysis. These were further subdivided into 9 studies for the CAD group and 11 studies for the CPD group. In the CAD intervention group, 53 shoulders in 7 studies were managed by 5 different head-preserving techniques. The choice of procedure to stabilize the shoulder after open reduction varied between coracoid transfer, capsulolabral repair, remplissage, and Putti-Platt procedure and acromiohumeral K-wire fixation. High resubluxation rates and early arthrosis were reported after open reduction techniques for CAD. In the CAD conservative group, 8 shoulders in 2 studies were managed by conservative methods. In the CPD group, the 2 most common techniques, McLaughlin or modified McLaughlin and bone grafting, were used to treat 74 shoulders in 7 studies and showed good functional outcomes. CONCLUSION: The choice of open reduction and stabilization technique for CAD was highly variable between the different studies and led to a wide variation in the reported outcomes with a high number of complications such as resubluxation and early arthrosis. The conservative treatment of CAD led to poor functional results. The choice of treatment for CPD was mostly between 2 techniques-McLaughlin and modified McLaughlin reconstruction or the bone graft reconstruction-and they consistently led to good functional outcomes with less complications.

An outlook on procedures of conjugating folate to (co)polymers and drugs for effective cancer targeting.

Folate receptors (FRs) are expressed in vast majority of cancers. Selective targeting of the FRs is, therefore, one of the most popular and sought-after strategies for improving the efficacy of cancer therapeutics. Variety of approaches involving folate conjugation to several well-known and novel, nontoxic, biodegradable, and biocompatible (co)polymers have been attempted and successfully applied to a large number of nanoparticulate drug delivery systems (micelles, liposomes, nanoparticles, quantum dots, mesoporous silica-based materials, and others) in the last decade-and-a-half. Standard and novel synthetic approaches were utilized for the conjugation, followed by the formulation of the drug delivery modality. In most of the cases, the targeted system lived up to its reputation, validating its usefulness in targeted cancer therapeutics. The present review summarizes the progress and state-of-the-art synthetic methodologies for folate conjugation to (co)polymers, drugs, and nucleic acids. The limitations of the FR targeting are discussed in brief to give the reader the other side of the story. Finally, the information on marketed folic acid conjugates highlight their industrial applications.